Many cell types in the body can remove apoptotic and cellular debris from tissues; however, the professional phagocyte, or antigen presenting cell (“APC”), has a high capacity to do so. The recognition of apoptotic cells (“ACs”) occurs via a series of evolutionarily-conserved, AC-associated molecular-pattern receptors (“ACAMPRs”) on APCs that recognize and bind corresponding apoptotic-cell-associated molecular patterns (“ACAMPs”). These receptors recognize ligands such as phosphotidyl serine and oxidized lipids found on apoptotic cells. Savill et al. (2002); and Gregory et al. (2004).
Both in vitro and in vivo that AC clearance by APCs in vivo regulates immune responses. Savill, et al. (2002). This immune modulation appears to occur primarily via an alteration of APC function with several hallmarks of a tolerance-inducing APC. These tolerogenic APCs induce tolerance via a variety of mechanisms including the generation of regulatory T cells (“Tregs”).
Tregs comprise a heterogeneous group of T lymphocytes, which actively inhibit immune responses. Groux et al. (1997); Sakaguchi et al. (2001); and Roncarolo et al. (2001). There is the potential to develop Treg therapies for a variety of diseases.
One way to generate Tregs in vivo is via the infusion of ACs. There is evidence from both animal models and human treatments that AC infusion, such as happens during extracorporeal photophoresis (“ECP”), induces Tregs. Maeda et al. (2005); Lamioni et al. (2005); Aubin et al. (2004); Mahnke et al. (2003); and Saas et al. (2002).
Other methods to generate Tregs ex vivo include exposing T cells to a variety of substances including: IL-10 (Roncarolo et al. (2001); and Zeller et al. (1999)); TGFβ (Zheng et al. (2004); Gray et al. (1998); Horwitz et al. (1999); Ohtsuka et al. (1999a); Ohtsuka et al. (1999b); Stohl et al. (1999); Gray et al. (2001); Horwitz, (2001); Yamagiwa et al. (2001); Horwitz et al. (2002); and Zheng et al. (2002)); αMSH (Luger et al. (1999); Taylor (2005); Namba et al. (2002); Nishida et al. (1999); Nishida et al. (2004); Streilin et al. (2000); Taylor et al. (1992); Taylor et al. (1994a); Taylor et al. (1994b); Taylor et al. (1996); Taylor (1999); Taylor (2003); and Taylor et al. (2003)); vitamin D3 (Willheim et al. (1999); Penna et al. (2000); Pedersen et al. (2004); May et al. (2004); Koren et al. (1989); Gregori et al. (2001); Cobbold et al. (2003); and Barrat et al. (2002)); dexamethasone (Pedersen et al. (2004); Barrat et al. (2002); and O'Garra et al. (2003)); and purification (Earle et al. (2005); Schwarz et al. (2000); Chatenoud et al. (2001); Tang et al. (2004); and Masteller et al. (2005)).
Autoimmune diseases involve inappropriate activation of immune cells that are reactive against self tissue. These activated immune cells promote the production of cytokines and autoantibodies involved in the pathology of the diseases. Other diseases involving T-cells include Graft versus Host Disease (GVHD) which occurs in the context of transplantation. In GVHD donor T-cells reject recipient's tissues and organs by mounting an attack against the recipient's body. A host of other diseases involve disregulation of the host immune system. Some are best treated with pharmaceuticals, some with biologicals, others with treatments such as extracorporeal photophoresis (ECP), and yet others have very limited treatment options.
ECP has been shown to be an effective therapy in certain T cell-mediated diseases. In the case of GVHD, photopheresis has been used as a treatment in association with topical triamcinolone ointment, antifungal, antiviral, antibiotics, inimunoglobulins, and methotrexate. ECP has also been used with immunosuppressive agents such as mycophenolate mofetil, tacrolimus, prednisone, cyclosporine, hydroxychloroquine, steroids, FK-506, and thalidomide for chronic GVHD (“cGVHD”) and refractory cGVHD. For solid organ transplants, ECP has been used in conjunction with immunosuppressive agents to reduce the number of acute allograft rejection episodes associated with renal allografts and cardiac tranplants. For example, ECP has been used with OKT3 and/or the immunosuppressive agents prednisone, azathioprine, and cyclosporine to reverse acute renal allograft rejection. ECP has also been used with cyclophosphamide, fractionated total body irradiation, and etoposide for allogeneic marrow transplantation for acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, non-Hodgkin's lymphoma,; or severe aplastic anemia.